Project Summary Nicotinic ?4?2* receptors have been implicated in a number of pathophysiologies. At University of California- Irvine (UCI) and University of Wisconsin-Madison (UWM), we have several major programs that would gain from imaging nicotinic receptors. These include: 1) Program in aging and neurodegenerative disorders; 2) Program on studies related to nicotine dependence; 3) Program in the early detection of lung cancer, and 4) Neurobiology of learning and memory. During the previous 3-year funding period we have successfully completed initial human PET studies (test-retest and radiation dosimetry) with [18F]Nifene with the following outcomes: 1) [18F]Nifene requires a 40 min dynamic scan for quantitation; 2) Urinary bladder is the critical organ, and 4 PET studies with 5 mCi injections can be done annually; 3) Nifene measures ?4?2, ?3?2 and ?2?2 receptor subtypes; 4) Nifene is a partial agonist; 5) [18F]Nifene is able to detect thalamic radiations (white matter tracts); 6) Females show greater [18F]Nifene binding than males; and 7) No aging effect on [18F]Nifene binding was observed. Since the initial study included only 8 subjects, a larger group of subjects is required in order to confirm the findings of male-female differences and aging using [18F]Nifene. In this 3-year renewal application our goals are: 1) Confirm male-female differences using 32 healthy subjects (16M, 16F) and examine aging effects by grouping 16 (8M, 8F) in their 20?s and 16 (8M, 8F) in their 70?s in all brain regions. 2) In the second goal, in pursuit of translation of [18F]Nifene PET to study human neurodegeneration, we propose to study postmortem brains of Alzheimer?s disease (AD) and Parkinson?s disease (PD). Two brain areas have been chosen based on previous findings of their significance, anterior cingulate (with corpus callosum) and hippocampus (containing CA1/subiculum). These will be evaluated using [18F]Nifene in 3 groups: controls, AD and PD (32 subjects in each group, 16M, 16F). 3) The third goal is to evaluate degree of binding of [18F]Nifene to the receptor subtypes using knock-out (KO) mice. Both ?2 and ?4 KO will be studied using [18F]Nifene PET and autoradiography and a male-female and aging effect will be evaluated in wild-type (WT) mice. This renewal application will help to ascertain that females have greater levels of [18F]Nifene binding (greater availability of ?4?2* receptors), there is no aging effect on [18F]Nifene binding and whether there is a change in ?4?2* receptors in neurodegeneration in certain brain regions. Additionally, the mice studies using [18F]Nifene will provide information on receptor selectivity and similarities with humans in terms of gender effects and aging. These studies will be important and necessary to carry translational studies in neurodegeneration, both mice models and humans.